OBJECTIVE:To evaluate international and interprofessional variability in the definition and genetic evaluation of polyhydramnios, and to identify factors influencing clinical decision-making. METHOD:An international electronic survey was distributed to healthcare professionals, addressing definitions of polyhydramnios, criteria for recommending invasive diagnostic prenatal testing, and preferred genetic testing strategies. Responses were analyzed by geographic region and professional specialty. RESULTS:A total of 154 clinicians from diverse regions completed the survey. Most defined polyhydramnios using absolute ultrasound values rather than percentiles. While 17.8% recommended invasive diagnostic testing for any pregnancy with polyhydramnios, 41.8% did so only when additional anomalies were present. Maternal-fetal medicine specialists were less likely to recommend invasive diagnostic testing (e.g., amniocentesis), particularly for mild isolated cases, whereas geneticists and genetic counselors were more likely to recommend prenatal genetic testing. US-based respondents were more likely to recommend only fetal chromosome analysis, whereas Israeli respondents tended to recommend advanced molecular diagnostics even in isolated cases. CONCLUSION:Substantial variability was noted in the genetic evaluation of polyhydramnios, driven by specialty and geographic factors. These findings highlight the absence of a consistent evidence base and underscore the need for studies defining diagnostic yield by clinical scenario and testing modality to inform evidence-based decision-making, while recognizing that practice patterns also reflect local resources and healthcare systems.

OBJECTIVE:To explore potential genetic contributors across different subtypes of isolated neural tube defects (NTDs) - acrania-exencephaly-anencephaly sequence (AEAS), spinal dysraphism, and encephalocele - using exome sequencing (ES) in a prenatal cohort, with the goal of gaining insight into the molecular diversity underlying these distinct phenotypes. METHODS:We retrospectively reviewed all fetuses diagnosed prenatally with isolated NTDs at Tel Aviv Sourasky Medical Center between September 2020 and July 2025. Detailed anatomical ultrasound excluded additional malformations. Chromosomal microarray (CMA) and trio-based ES were performed using standard protocols. Variant interpretation followed ACMG/AMP guidelines, integrating phenotypic concordance via Human Phenotype Ontology (HPO) terms. RESULTS:The cohort comprised 23 fetuses: 10 with AEAS (9 acrania, 1 exencephaly), 8 with spinal dysraphism (5 myelomeningocele, 3 meningocele), and 5 with encephalocele. Across the cohort, exome sequencing yielded pathogenic or likely pathogenic variants in 26% (6/23) of cases and a variant of uncertain significance in 4% (1/23). Detection rates varied by subtype, highest in encephalocele (60%), followed by spinal dysraphism (25%) and AEAS (20%). However, these findings reflect diagnostic associations rather than definitive causal relationships. Identified genes included PPP1R12A, ARHGAP35, PIEZO2, KIAA0586, TSC2, and CLCN7, representing diverse pathways in cytoskeletal organization, ciliary function, mechanotransduction, and mTOR signaling. Notably, recurrent PPP1R12A variants were found in 2 fetuses: one with AEAS and one with encephalocele, suggesting a shared morphogenetic pathway affecting cranial fold formation and mesenchymal remodeling. CONCLUSION:Our findings indicate that these distinct types of NTD, namely AEAS, spinal dysraphism, and encephalocele, may represent partially divergent embryologic and genetic entities rather than a single phenotypic continuum. Subtype-specific analysis revealed differing molecular patterns, emphasizing the value of trio-based ES in elucidating the etiology of isolated NTDs. Larger studies are needed to refine detection rates and expand our understanding of the genetic architecture underlying these distinct malformations.

Rapid growth in genetic testing usage resulted in declining availability of genetic counselors (GCs) per ordered tests, prolonging the waiting times for face-to-face (F2F) counseling. We evaluated the digital genetic assistant (DGA) for reproductive genetic carrier screening (RGCS) in a real-life clinical setting using a “couple-based” paradigm. The platform provides digital patient intake and automated counseling for low-risk individuals, as well as GC-facing tools that reduce administrative burden in patient-related activities. Among 225 couples undergoing RGCS during the study period, 4% had high-risk results requiring F2F counseling and an additional 4% of low-risk couples requested F2F counseling, suggesting that DGA use reduced GC-participant F2F interactions by 69.3%. GC evaluations revealed that the DGA triaging algorithm was accurate and surveys demonstrated high degrees of user comprehension and satisfaction. These results highlight the utility of digital platforms for patient intake and delivery of low-risk results in settings with limited genetic counseling resources.

OBJECTIVE:Fetal macrocephaly (HC Z-score ≥ +2) is a common reason for referral for neurosonography. While most cases are benign and asymptomatic, syndromic macrocephaly poses a significant risk of abnormal neurodevelopment. This study aimed to describe the sonographic and genetic features of fetuses at the highest risk of syndromic macrocephaly. METHODS:We retrospectively analyzed 19 fetuses with either HC Z-scores ≥ +2.5 or those with ≥ +2 and associated anomalies, evaluated between January 2015 and October 2024. Assessments included fetal neurosonography, anomaly scans, MRI, and genetic work-up. Outcomes and postnatal/postmortem data were reviewed. RESULTS:Mean gestational age at the time of diagnosis was 29.6 weeks (range 23-35.4 weeks). Seventeen fetuses (89%) had associated anomalies: large for gestational age (12/19), callosal abnormalities (11/19), malformation of cortical development (13/19), and facial dysmorphism (11/19) were diagnosed. Genetic investigation results (CMA) were available for 17 of the 19 patients. Overall, 14 of the 17 patients had abnormal genetic findings, mostly involving mTOR pathway genes. CONCLUSION:High Z-scores and additional imaging findings strongly correlate with genetic abnormalities, most often mTOR-related. These results support the integration of exome sequencing into prenatal evaluation of fetal macrocephaly.

OBJECTIVE:To evaluate the diagnostic yield of exome sequencing (ES) in isolated polyhydramnios. METHODS:This retrospective study included 40 cases of isolated polyhydramnios. All patients underwent screening for gestational diabetes mellitus (GDM) and chromosomal microarray analysis (CMA). ES was performed in CMA-negative cases, along with targeted testing for spinal muscular atrophy, myotonic dystrophy type 1, and Prader-Willi syndrome. RESULTS:Pathogenic or likely pathogenic variants were identified in 7 cases, yielding a 17.5% diagnostic rate. Diagnostic yield was 12% (2/17) in mild cases and 22% (5/23) in moderate-severe cases. Diagnoses included Bartter syndrome (KCNJ1, BSND, MAGED2), Noonan syndrome (RIT1), Osteopathia Striata with Cranial Sclerosis (AMER1), and AUTS2-related neurodevelopmental disorder. In addition, one case was diagnosed postnatally with myotonic dystrophy 1. Two ES-positive cases had concurrent GDM. Postnatal follow-up showed normal development in 85% of live-born infants, with a few cases of global or speech delay. CONCLUSIONS:ES yields a substantial diagnostic benefit in isolated polyhydramnios, including mild cases and those with GDM. These findings support incorporating ES into the diagnostic approach for isolated polyhydramnios.

Over 200 pathogenic variants in the OTOF gene encoding otoferlin are associated with sensorineural hearing loss (SNHL) and auditory neuropathy spectrum disorders (ANSD). A novel splice variant, OTOF c.898-18G > A, was detected in seven Jewish Moroccan families with both SNHL and ANSD in an Israeli multicenter study. The effect on splicing was confirmed by a minigene assay, which demonstrated skipping of exon 10. This variant is absent in gnomAD and in all Jewish ethnic groups except for Moroccan Jews, with a carrier rate of 1.5

BACKGROUND:As advanced molecular testing is incorporated into routine clinical practice, accessibility and yield remain limited. OBJECTIVES:We propose a simplified and effective workup strategy to maximize diagnostic yield based on presented diagnostic yield of rare movement disorders at a tertiary Neurogenetics Clinic. METHODS:Retrospective analysis (2019-2023) of 190 patients aged 2-87 years, diagnosed with cerebellar ataxia (CA, n = 91), hereditary spastic paraparesis (HSP, n = 51), or dystonia and paroxysmal dyskinesia movement disorders (DPD, n = 48). Workup included next-generation sequencing (NGS) and repeat expansion testing. Undiagnosed cases underwent exome or genome sequencing (ES/GS). RESULTS:Among 190 patients, 38 had a prior genetic diagnosis, and 106 were undiagnosed patients who pursued workup; 43 of 106 (41%) cases were genetically diagnosed: 25 of 43(58%) by NGS, 13 of 43 (30%) by repeat expansion analysis, and 5 of 43(12%) by sequencing for founder mutation or target gene. Diagnostic rate in the newly diagnosed CA subgroup reached 52%, 30% in HSP and 32% in DPD. In the overall cohort, the diagnostic yield of NGS panels was 31% and 33% for ES. Diagnostic yield was significantly higher (P-value<0.05) among patients with early-onset disease or isolated phenotypes. CONCLUSIONS:We report a high diagnostic yield (41%) compared to reported literature (20%-30%), especially in patients with early-onset disease. ES, compared to panel testing, was of greater contribution to diagnosis of complex phenotypes. Our findings argue for early referral to genetic workup, suggesting that tailored workup based on phenotype complexity and age of onset can reduce auxiliary testing. Further cost-benefit analysis is required to lower expenses and ensure timely diagnosis.

The authors declare no conflicts of interest. Data related to the study are available upon reasonable request from the corresponding author.

Defective neuronal migration causes lissencephaly (LIS), a neurodevelopmental disorder (NDD) with a smooth cerebral surface and abnormal cortical thickness. Variants in CEP85L are linked to posterior predominant LIS, but the phenotype and genotype are unclear. Three new unrelated cases of CEP85L-associated LIS are presented, including the first prenatal diagnosis and a mosaic variant. Clinical, neuroimaging, and genetic analyses were recorded. Data from 29 previously reported individuals was used in a comprehensive literature review. Human phenotype ontology (HPO) terms were used to annotate phenotypic features, and American College of Medical Genetics and Genomics (ACMG) guidelines were used to evaluate variants. All postnatal individuals had variable NDD. Global developmental delay was observed in 71 % (22/31), speech or motor delay in 54 % (11/31 and 6/31, respectively), and intellectual disability in 74 % (23/31) of cases. Focused and generalized-onset seizures occurred in 90 % (28/31). Brain magnetic resonance imaging (MRI) revealed predominantly posteriorly predominant LIS in all evaluated individuals, with 55 % (17/31) of cases also exhibiting subcortical band heterotopia (SBH). A total of 18 different CEP85L variants were identified among all individuals, all clustering in a highly conserved N-terminal region between amino acids 1 and 103. These included 10 missense mutations, five splice-site alterations, two start-loss variants, and one stop variant. Nine de novo variants, 10 mother-father variants, and 13 variants with unknown inheritance. Genotype-phenotype correlations in CEP85L-associated LIS show that stronger splice and germline variants often cause more severe symptoms than mosaic variants. To reduce confusion caused by alternative CEP85L transcripts, we recommend NM_001042475 for variant interpretation. These findings improve this disorder's genetic diagnostics and counseling framework.

Following termination of pregnancy due to multiple brain malformations, a non-consanguineous couple of Jewish descent sought genetic counseling. Brain malformations identified on neurosonogram included corpus callosum dysgenesis, abnormal brain stem morphology, abnormal cortical sulcation and hypertelorism. Trio exome sequencing revealed a heterozygous de novo likely pathogenic variant in KIDINS220 gene. Heterozygous variants in KIDINS220 have been linked to spastic paraplegia, intellectual disability, nystagmus, and obesity syndrome (SINO). Reports on prenatal findings are limited and primarily consist of cases of ventriculomegaly. We describe a more severe clinical presentation in a case with a heterozygous variant.

ABSTRACT Objective Mitochondrial complex‐I deficiency, nuclear type 16, is a rare autosomal recessive disorder caused by biallelic pathogenic variants in NDUFAF5 ( C20orf7 ) (OMIM 618238). The aim of this study was to describe a severe early prenatal manifestation of this disorder, which was previously considered to occur only postnatally. Methods This was a multicenter retrospective case series including five fetuses from three non‐related families, which shared common sonographic abnormalities, including brain cysts, corpus callosal malformations, non‐immune hydrops fetalis and growth restriction. Genetic evaluation included chromosomal microarray analysis and exome sequencing. Two fetuses from the same family were also available for pathology examination, including electron microscopy. Results Chromosomal microarray analysis revealed no chromosomal abnormality in any of the tested cases. Trio exome sequencing demonstrated that three affected fetuses from three unrelated families were compound heterozygous or homozygous for likely pathogenic variants in NDUFAF5 . No other causative variants were detected. The association between NDUFAF5 variants and fetal malformations was further confirmed by segregation analysis. Histological evaluation of fetal tissues and electron microscopy of the skeletal muscle, liver, proximal tubules and heart demonstrated changes that resembled postmortem findings in patients with mitochondrial depletion disorders as well as previously undescribed findings. Conclusions Mitochondrial complex‐I deficiency and specifically biallelic mutations in NDUFAF5 have a role in abnormal fetal development, presenting with severe congenital malformations. Mitochondrial complex‐I disorders should be considered in the differential diagnosis of corpus callosal malformations and brain cysts, especially when associated with extracranial abnormalities, such as fetal growth restriction and non‐immune hydrops fetalis. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder. It is mostly sporadic, with the C9orf72 repeat expansion being the most common genetic cause. While the prevalence of C9orf72-ALS in patients from different populations has been studied, data regarding the yield of C9orf72 compared to an ALS gene panel testing is limited. We aimed to explore the application of C9orf72 versus a gene panel in the general Israeli population. A total of 140 ALS patients attended our Neurogenetics Clinic throughout 2018–2023. Disease onset was between ages 60 and 69 years for most patients (34